CN1307580A - Syntheses of variety of lamellarin compounds and analogues - Google Patents

Syntheses of variety of lamellarin compounds and analogues Download PDF

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CN1307580A
CN1307580A CN99807867A CN99807867A CN1307580A CN 1307580 A CN1307580 A CN 1307580A CN 99807867 A CN99807867 A CN 99807867A CN 99807867 A CN99807867 A CN 99807867A CN 1307580 A CN1307580 A CN 1307580A
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M·G·班维尔
B·L·弗莱恩
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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Abstract

The present invention relates to methods for preparing a variety of Lamellarin compounds and analogues via a synthetic intermediate, which methods involved the step of performing an intramolecular cyclization of a compound of Formula (I) to produce compounds of Formula (II), wherein the variables are given in the specification.

Description

Plain compound of various spiral shells and analogue synthetic
Invention field
The present invention relates generally to the intermediate of the compound that can be used for treating.More specifically, the present invention relates to prepare the intermediate of the thick polycyclic alcaloid of a class.The present invention also relates to prepare the method for thick polycyclic alcaloid and analogue and derivative.
Background of invention
The natural molecule that exists that shows useful pharmacological properties potentially can be from nature, and as the ocean, plant and microorganism are separated.An example of this quasi-molecule is the total class with sheet spiral shell element (Lamellarins) compound known.These how fragrant alkaloids are separated from the ocean, and comprise the many aromatic structures of condensed.Plain C of sheet spiral shell and D have demonstrated in the analysis of fertilization sea urchin and have caused fissional inhibition, and the plain I of sheet spiral shell, K and L demonstrate when cultivating has suitable significant cytotoxicity to P388 and A549 clone.Recently, the plain N of sheet spiral shell is by demonstrating activity as IV type microtubule poison in lung cancer cell line.And these compounds have also demonstrated has cytotoxicity to the multidrug-resisting cell, and can be used as the nontoxic conditioning agent of multidrug-resisting phenotype, and therefore a kind of potential source of attractive chemotherapeutics is provided.
But the potential clinical application of sheet spiral shell element is subjected to its limited natural output, and the serious restriction of separation difficulty.
Therefore, people have very high enthusiasm for the route of synthesis of this quasi-molecule of exploitation, comprise 1 for the method for these molecules, 3,4-triaryl-the 2, (Steglich etc. of dicycloization successively of the pyrrole ring that the 5-dicarboxyl replaces, Angew.Chem.Int.Ed.Eng.1997,36,155) and the pyrrole ring of N-ylide-mediation form, the pyrroles and the lactone part (Banwell etc. of this molecule are installed, Chem.Commun., 1997,2259; Ishibashi etc., Tetrahedron, 1997,53,5951).
The present invention provides the other method through synthetic intermediate now, and this method allows to replace the doping of type scope, and consent tacitlys to plain compound of various spiral shells and the homologue that contains thick many ring-pyrroles's cores.
Disclosure of the Invention
First aspect the present invention relates to prepare the method for general formula (II) compound: Comprise the intramolecular cyclization step of carrying out formula (I) compound:
Figure A9980786700132
R wherein A1-A4Be selected from hydrogen independently of one another, the alkyl of non-imposed replacement, the thiazolinyl of non-imposed replacement, the alkynyl of non-imposed replacement, the hydroxyl of non-imposed protection, the amino of non-imposed replacement, the alkoxyl group of non-imposed replacement, the alkene oxygen base of non-imposed replacement, the alkynyloxy group of non-imposed replacement, the aryl of non-imposed replacement, the heterocyclic radical of non-imposed replacement, carboxyl, carboxyl ester group, amide group, acyl group, acyloxy, sulfydryl, the alkylthio of non-imposed replacement, halogen, nitro, sulfate radical, phosphate radical and cyano group; Or R A2And R A3Form a key together non-imposedly, and R A1And R A4As above definition or form the saturated or unsaturated carbocyclic or the heterocyclic radical of non-imposed replacement with the carbon atom that it connected; Or R A2And R A3Form the carbocyclic ring or the heterocyclic radical of non-imposed replacement with the carbon atom that it connected non-imposedly; Or R A1R A2C-CR A3R A4Form the aryl or the fragrant heterocyclic radical of non-imposed replacement; Y is selected from hydrogen, the alkyl of non-imposed replacement, the thiazolinyl of non-imposed replacement, the alkynyl of non-imposed replacement, the hydroxyl of non-imposed protection, the amino of non-imposed replacement, the alkoxyl group of non-imposed replacement, the alkene oxygen base of non-imposed replacement, the alkynyloxy group of non-imposed replacement, the aryl of non-imposed replacement, the heterocyclic radical of non-imposed replacement, carboxyl, the carboxyl ester group, amide group, acyl group, acyloxy, sulfydryl, the alkylthio of non-imposed replacement, halogen, nitro, sulfate radical, phosphate radical and cyano group; The definition of W and X such as Y perhaps forms saturated or undersaturated nitrogen heterocycle with nitrogen and the carbon atom that it connected, and this heterocyclic radical can be substituted non-imposedly, or non-imposed and saturated or undersaturated carbocylic radical, and aryl or heterocyclic radical condense; V represents halogen or hydrogen atom; Z is-(CH 2) n-U-(CH 2) o-wherein U is selected from CH 2, NH or heteroatoms, n and o are independently selected from 0,1, and 2 or 3.
Second aspect the invention provides the intermediate that can be used for preparation formula (II) compound, and wherein said intermediate is the compound of formula (I):
Figure A9980786700141
Wherein:
R A1-A4Be selected from hydrogen independently of one another, the alkyl of non-imposed replacement, the thiazolinyl of non-imposed replacement, the alkynyl of non-imposed replacement, the hydroxyl of non-imposed protection, the amino of non-imposed replacement, the alkoxyl group of non-imposed replacement, the alkene oxygen base of non-imposed replacement, the alkynyloxy group of non-imposed replacement, the aryl of non-imposed replacement, the heterocyclic radical of non-imposed replacement, carboxyl, carboxyl ester, amide group, acyl group, acyloxy, sulfydryl, the alkylthio of non-imposed replacement, halogen, nitro, sulfate radical, phosphate radical and cyano group; Or R A2And R A3Form a key together non-imposedly, and R A1And R A4As above definition or form the carbocyclic ring or the heterocyclic radical of non-imposed replacement with the carbon atom that it connected; Or R A2And R A3Form the saturated or unsaturated carbocyclic or the heterocyclic radical of non-imposed replacement with the carbon atom that it connected non-imposedly; Or R A1R A2C-CR A3R A4Form the aryl or the fragrant heterocyclic radical of non-imposed replacement; Y is selected from hydrogen, the alkyl of non-imposed replacement, the thiazolinyl of non-imposed replacement, the alkynyl of non-imposed replacement, the hydroxyl of non-imposed protection, the amino of non-imposed replacement, the alkoxyl group of non-imposed replacement, the alkene oxygen base of non-imposed replacement, the alkynyloxy group of non-imposed replacement, the aryl of non-imposed replacement, the heterocyclic radical of non-imposed replacement, carboxyl, the carboxyl ester group, amide group, acyl group, acyloxy, sulfydryl, the alkylthio of non-imposed replacement, halogen, nitro, sulfate radical, phosphate radical and cyano group; The definition of W and X such as Y perhaps forms saturated or undersaturated nitrogen heterocycle with nitrogen and the carbon atom that it connected, and this heterocyclic radical can be substituted non-imposedly, or non-imposed and saturated or undersaturated carbocylic radical, and aryl or heterocyclic radical condense; V represents halogen or hydrogen atom; Z is-(CH 2) n-U-(CH 2) o-wherein U is selected from CH 2, NH or heteroatoms, n and o are independently selected from 0,1, and 2 or 3.
The present invention also relates in one aspect to formula (II) compound by method preparation as herein described.
Term used herein " alkyl " refers to straight chain, the full saturated hydrocarbyl of side chain or ring-type.Unless carbonatoms is specific, otherwise this term preferably refers to C 1-20Alkyl or cycloalkyl.The example of straight or branched alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, sec.-amyl sec-pentyl secondary amyl, 1,2-dimethyl propyl, 1,1-dimethyl propyl, hexyl, 4-methyl amyl, 1-methyl amyl, 2-methyl amyl, 3-methyl amyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3, the 3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylammonium propyl group, 1,1,2-trimethylammonium propyl group, heptyl, 5-methoxyl group hexyl, 1-methyl hexyl, 2,2-dimethyl amyl group, 3,3-dimethyl amyl group, 4,4-dimethyl amyl group, 1,2-dimethyl amyl group, 1,3-dimethyl amyl group, 1,4-dimethyl amyl group, 1,2,3-trimethylammonium butyl, 1,1,2-trimethylammonium butyl, 1,1,3-trimethylammonium butyl, octyl group, 6-methylheptyl, 1-methylheptyl, 1,1,3,3-tetramethyl butyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-Methyl Octyl, 1-, 2-, 3-, 4-or 5-ethyl heptyl, 1-, 2-or 3-propyl group hexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-or 8-methyl nonyl, 1-, 2-, 3-, 4-, 5-or 6-ethyl octyl group, 1-, 2-, 3-or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-methyl decyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-ethyl nonyl, 1-, 2-, 3-, 4-or 5-propyl group octyl group, 1-, 2-or 3-butyl heptyl, 1-amyl group hexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-or 10-methyl undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-or 8-ethyl decyl, 1-, 2-, 3-, 4-, 5-or 6-propyl group nonyl, 1-, 2-, 3-or 4-butyl octyl, 1-, 2-amyl group heptyl or the like.That the example of cycloalkyl comprises is single-or multi-ring alkyl, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl or the like.
Term used herein " thiazolinyl " refers to from straight chain, and side chain or cyclic hydrocarbon group form, and contains the group of at least one carbon-to-carbon double bond, comprise the list of alkylene-, two-or many-undersaturated alkyl or cycloalkyl as preceding definition.Unless carbonatoms is specific, otherwise this term preferably refers to C 1-20Thiazolinyl.The example of thiazolinyl comprises vinyl, allyl group, 1-methyl ethylene, butenyl, isobutenyl, 3-methyl-2-butene base, 1-pentenyl, cyclopentenyl, 1-methyl cyclopentene base, 1-hexenyl, the 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, the cyclooctene base, 1-nonene base, 2-nonene base, 3-nonene base, the 1-decene base, 3-decene base, 1,3-butadiene base, 1,4-pentadienyl, 1 base, 1,3-hexadienyl, 1,4-hexadienyl, the 1 base, the 1 base, 1,3-cycloheptadiene base, 1,3,5-cycloheptatriene base and 1,3,5,7-cyclooctatetraene base.
Term used herein " alkynyl " refers to from containing the straight chain of at least one carbon-to-carbon triple bond, the group that side chain or cyclic hydrocarbon group produce, comprise the list as preceding definition of ethynylation-, two-or many-unsaturated alkyl or cycloalkyl.Unless carbonatoms is specific, otherwise this term preferably refers to C 1-20Alkynyl.Example comprises ethynyl, 1-proyl, 2-propynyl and butynyl isomer and pentynyl isomer.
Term " alkoxyl group ", " alkene oxygen base " and " alkynyloxy group " refer to the alkyl as preceding definition that is connected with oxygen, thiazolinyl and alkynyl respectively.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Term " aryl " refers to list, multinuclear, the residue of conjugation and condensed aromatic ring.The example of aryl comprises phenyl, xenyl, terphenyl, tetrad phenyl, naphthyl, tetralyl, anthryl, dihydro anthryl, benzo anthryl, dibenzo anthryl, phenanthryl, fluorenyl, pyrenyl, idenyl, Azulene base, cave base.
Term " heterocycle " refers to that wherein at least one carbon atom preferably is selected from nitrogen, the heteroatoms metathetical list of sulphur and oxygen-or many carbocylic radicals.Wherein at least one carbon atom is called as fragrant heterocyclic radical by heteroatoms metathetical list-or many carbocylic radicals when being aryl.
Suitable heterocyclic radical comprises nitrogen heterocycle, as contains undersaturated 3 to 6 Yuans assorted monocycles of 1 to 4 nitrogen-atoms, for example, and pyrryl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl or tetrazyl; 3 to the 6 Yuans saturated assorted monocycles that contain 1 to 4 nitrogen-atoms, for example, pyrrolidyl, imidazolidyl, piperidyl, pyrazolidyl or piperazinyl; What contain 1 to 5 carbon atom condenses saturated or the unsaturated heterocycle base, as indyl, and pseudoindoyl, indolinyl, dihydro-iso indolyl, indolizine base, different indolizine base, benzimidazolyl-, quinolyl, isoquinolyl, indazolyl, benzotriazole base, purine radicals, quinazolyl, quinoxalinyl, phenanthridinyl, the phenanthroline base, 2 base, 1, the 5-phthalazinyl, cinnolines base, pteridine radicals, perimidinyl or tetrazolo pyridazinyl; 3 to the 6 Yuans saturated assorted monocycles that contain 1 to 3 Sauerstoffatom, as tetrahydrofuran base, THP trtrahydropyranyl, the dioxane base contains unsaturated 3 to 6 Yuans heteromonocyclic groups of a Sauerstoffatom, as pyranyl, oxine base or furyl; What contain 1 to 3 Sauerstoffatom condenses saturated or the unsaturated heterocycle base, as benzofuryl, and chromenyl or xanthenyl; Unsaturated 3 to the 6 Yuans heteromonocyclic groups that contain 1 to 2 sulphur atom are as thienyl or two sulphur fen bases; Unsaturated 3 to the 6 Yuans heteromonocyclic group ， such as the oxazolyl ， oxazolinyl ， isoxazolyl that contain 1 to 2 Sauerstoffatom and 1 to 3 nitrogen-atoms, furazan Ji Huo oxadiazole base; Saturated 3 to the 6 Yuans heteromonocyclic groups that contain 1 to 2 Sauerstoffatom and 1 to 3 nitrogen-atoms are as morpholinyl; The unsaturated fused heterocycle base that contains 1 to 2 Sauerstoffatom and 1 to 3 nitrogen-atoms is as benzoxazolyl or Ben Bing oxadiazole base; Unsaturated 3 to the 6 Yuans heteromonocyclic groups that contain 1 to 2 sulphur atom and 1 to 3 nitrogen-atoms, as thiazolyl, thiazolinyl or thiadiazolyl group; Saturated 3 to the 6 Yuans heteromonocyclic groups that contain 1 to 2 sulphur atom and 1 to 3 nitrogen-atoms are as thiazolidyl; With the unsaturated fused heterocycle base that contains 1 to 2 sulphur atom and 1 to 3 nitrogen-atoms, as benzothiazolyl or diazosulfide base.
Term " acyl group " refer to wherein OH by for example to W, the residue metathetical carboxylic acid residues of X and Y definition; can refer to formamyl particularly, aliphatic acyl or contain the acyl group of aromatic nucleus is called as aromatic acyl group; or contain the heterocyclic acyl group, be called as heterocyclic acyl, preferred C 1-20Acyl group.The example of suitable acyl group comprises formamyl; Straight or branched alkyloyl such as formyl radical, ethanoyl, propionyl, butyryl radicals, the 2-methylpropionyl, pentanoyl, 2,2-dimethyl propylene acyl group, caproyl, oenanthyl, capryloyl, nonanoyl, decanoyl, undecanoyl, lauroyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, the heptadecane acyl group, octadecanoyl, nonadecane acyl group and eicosane acyl group; Carbalkoxy such as methoxycarbonyl, ethoxycarbonyl, tertbutyloxycarbonyl, uncle's penta oxygen carbonyl and heptan the oxygen carbonyl; Naphthene base carbonyl such as cyclopropyl carbonyl, cyclobutyl carbonyl, cyclopentylcarbonyl and cyclohexyl-carbonyl; Alkyl sulphonyl such as methylsulfonyl and ethylsulfonyl; Alkoxyl group alkylsulfonyl such as methoxyl group alkylsulfonyl and oxyethyl group alkylsulfonyl; Aroyl such as benzoyl, toluyl and naphthoyl; Aralkoxy such as octadecyloxy phenyl acyl group (for example phenyl acetyl, phenyl propionyl, phenyl butyryl radicals, phenyl isobutyryl, phenyl pentanoyl and phenyl caproyl) and naphthyl alkyloyl (for example naphthyl ethanoyl, naphthyl propionyl and naphthyl acyl group); Virtue enoyl-such as phenyl enoyl-(phenyl acryloyl for example, phenyl crotonoyl, phenyl methacryloyl, phenyl pentenoyl and phenyl hexenoyl and naphthyl enoyl-(for example naphthyl acryl, naphthyl enoyl-and naphthyl pentenoyl); Aralkoxycarbonyl such as phenyl carbalkoxy (for example carbobenzoxy-(Cbz)); Aryloxy carbonyl such as carbobenzoxy and naphthalene oxygen carbonyl; Aryloxy group alkyl acyl group such as phenoxy group ethanoyl and phenoxy group propionyl; Aryl-amino-carbonyl such as phenyl amino formyl radical; Arylthio formamyl such as thiophenyl formamyl; Aryl is glyoxyl-based glyoxyl-based glyoxyl-based with naphthyl as phenyl; Aryl sulfonyl such as phenyl sulfonyl and naphthyl alkylsulfonyl; The heterocycle carbonyl; Heterocycle alkyloyl such as thienyl ethanoyl, thienyl propionyl, thienyl butyryl radicals, thienyl pentanoyl, thienyl caproyl, thiazolyl ethanoyl, thiadiazolyl group ethanoyl and tetrazyl ethanoyl; Heterocycle enoyl-such as heterocycle acryl, heterocycle crotonoyl, heterocyclic pentene acyl group and heterocycle hexenoyl; Glyoxyl-based glyoxyl-based glyoxyl-based with heterocycle with thienyl as thiazolyl.
Term " acyloxy " refers to the acyl group as preceding definition that is connected with oxygen.
In this manual, " non-imposed replacement " meaning is selected from by alkyl thiazolinyl, alkynyl by one or more; aryl, halogen, haloalkyl, haloalkenyl group; the halo alkynyl, halogenated aryl, hydroxyl, alkoxyl group; alkene oxygen base, aryloxy, benzyloxy, halogenated alkoxy; haloalkene oxygen base, halo aryloxy, nitro, 4-nitro alkyl; the nitro thiazolinyl, nitro alkynyl, nitro aryl, nitro heterocyclic radical; amino, alkylamino, dialkyl amido, alkenyl amino; alkynyl amino, arylamino, ammonia diaryl base, benzylamino; dibenzyl amino, acyl group, thiazolinyl acyl group, alkynyl acyl group; aryl-acyl, acyl amino, diacylamino group, acyloxy; alkylsulfonyloxy, aryl-sulfonyl oxygen, heterocyclic radical; heterocyclic oxy group; heterocyclic amino group; the halogenated heterocyclic base; alkyl sulphinyl; aryl sulfonyl kia, carbalkoxy; aryloxy carbonyl, sulfydryl, alkylthio; benzylthio-, acyl sulfenyl, cyano group; nitro, one group of group that sulfate radical and phosphate radical are formed further replaces, or does not replace or condense (forming thick many cyclic groups).Term " non-imposed protection " refers to can protect or can not protect by protected base such as the group of hydroxyl.Suitable blocking group is known, and its example is at Protective Groups inOrganic Synthesis, by T.W.Greene (1981), and John Wiley ﹠amp; Describe among the Son.
" heteroatoms " used herein refers to it can is cyclic organic compounds member's any atom except that carbon atom.Suitable heteroatomic example comprises nitrogen, oxygen, sulphur, phosphorus, boron, silicon, arsenic, selenium and tellurium, especially nitrogen, oxygen and sulphur.
In formula (I) with (II) in the preferred version of compound, U as defining among the Z, is selected from CH 2One of, NH, in oxygen or the sulphur.More preferably, U is NH or oxygen.Most preferably, U is an oxygen.In another preferred version of Z, n+o=0,1,2,3 or 4.The suitable example of Z comprises-O-CH 2-,-CH 2-N-,-O-CH 2-O-,-(CH 2) 3-,-CH 2-NH-CH 2-or-CH 2-O-CH 2-.In another preferred version, n and o are 0.
In another preferred form, V is a hydrogen, iodine or bromine.
In another formula (I) and scheme (II), when W and X with nitrogen that they were connected with carbon atom forms saturated or during the unsaturated heterocycle base, this group is the quinolyl of non-imposed replacement preferably, the isoquinolyl of non-imposed replacement, the dihydroquinoline base of non-imposed replacement, the dihydro-isoquinoline base of non-imposed replacement, the pyridyl of non-imposed replacement or its dihydro or tetrahydrochysene homologue, or the phenanthridines of non-imposed replacement.Preferably, the isoquinolyl of W and the X non-imposed replacement that forms formula (i) with nitrogen that they were connected and carbon atom or the dihydro-isoquinoline base of non-imposed replacement:
Figure A9980786700201
R wherein 1-R 4And R 14As top Y definition, and
Figure A9980786700202
Expression singly-bound or two key.
Preferably, the R of formula (i) 1-R 4Be hydrogen; Hydroxyl; The alkyl of non-imposed replacement; The alkoxyl group of non-imposed replacement; Acyloxy; Carboxyl; Carboxylic acid ester groups, this ester methyl preferably wherein, ethyl, propyl group or butyl ester; The amino of non-imposed replacement; Amide group, wherein its nitrogen-atoms is independently selected from methyl by one or two, ethyl, the alkyl of propyl group or butyl replaces non-imposedly; Or sulfate radical.Most preferably, they are hydrogen, hydroxyl, methoxyl group, oxyethyl group, isopropoxy, methyl, ethyl, propyl group, acetoxyl group or sulfate radical.Preferably, R 14Be hydrogen or hydroxyl.
In formula (I) with (II) in another program of compound, work as R A1R A2C-CR A3R A4When forming aryl or fragrant heterocyclic radical, it can be the benzene or the naphthalene nucleus of a non-imposed replacement, or the fragrant heterocyclic radical of non-imposed replacement such as pyridine, furans, pyrroles or thiophene and its benzene-condensed homologue, for example, quinoline, indoles, cumarone and thionaphthene.Bicyclic heterocyclic radical can connect through benzene or heterocycle.R preferably A1R A2C-CR A3R A4Form the phenyl of non-imposed replacement.Substituting group is hydrogen preferably; Hydroxyl; The alkyl of non-imposed replacement; The alkoxyl group of non-imposed replacement; Acyloxy; Carboxyl; The carboxylic ester group, this ester methyl preferably wherein, ethyl, propyl group or butyl ester; The amino of non-imposed replacement; Formamido-, wherein its nitrogen-atoms is independently selected from methyl by one or two, ethyl, the alkyl of propyl group or butyl replaces non-imposedly; Or sulfate radical.Most preferably, they are hydrogen, hydroxyl, methoxyl group, oxyethyl group, isopropoxy, methyl, ethyl, propyl group, acetoxyl group or sulfate radical.
In another program, R A1-A4Preferably be independently selected from hydrogen, the alkyl of non-imposed replacement, the hydroxyl of non-imposed protection, the alkoxyl group of non-imposed replacement, the phenyl of non-imposed replacement or acyloxy.In another preferred scheme, R A1Or R A3At least one can be hydrogen.In another program, R A1And R A3All be hydrogen.In another program, R A1-A4In three or four be hydrogen.
In another program, work as R A2And R A3Form a key together, thereby form R A1C=CR A4The time, R A1And R A4Can be independently selected from hydrogen; Hydroxyl; The alkyl of non-imposed replacement; The alkoxyl group of non-imposed replacement; Acyloxy; Carboxyl; The carboxylic ester group, this ester methyl preferably wherein, ethyl, propyl group or butyl ester; The amino of non-imposed replacement; Formamido-, wherein its nitrogen-atoms is independently selected from methyl by one or two, ethyl, the alkyl of propyl group or butyl replaces non-imposedly.In particularly preferred form, R A1And R A4In one or both be hydrogen.
Work as R A2And R A3When forming as the carbocyclic ring of preceding definition or heterocyclic radical with the carbon atom that it connected, preferably form 3 to 8-person's cyclic group, preferred 5 to 6-person's cyclic group.Preferably, they form pentamethylene, hexanaphthene, cyclopentenes, tetrahydrobenzene, cyclopentadiene, cyclohexadiene, tetrahydrofuran (THF), dihydrofuran, tetramethyleneimine, pyrroline, pyrans, dihydropyrane, tetrahydropyrans or piperidyl.Preferably, R A1And R A4Be hydrogen.
In the scheme of going back, Y is the phenyl of formula non-imposed replacement (ii) preferably:
Figure A9980786700211
R wherein 9-R 13As above in the face of R 1-R 4And R 14Definition.
More preferably, R 9-R 13Be hydrogen; Hydroxyl; The alkyl of non-imposed replacement; The alkoxyl group of non-imposed replacement; Acyloxy; Carboxyl; The carboxylic ester group, this ester methyl preferably wherein, ethyl, propyl group or butyl ester; The amino of non-imposed replacement; Amide group, wherein its nitrogen-atoms is independently selected from methyl by one or two, ethyl, the alkyl of propyl group or butyl replaces non-imposedly; Or sulfate radical.Most preferably, R 9-R 13Be selected from hydrogen, hydroxyl, methoxyl group, oxyethyl group, isopropoxy, methyl, ethyl, n-propyl, sec.-propyl, acetoxyl group or sulfate radical.
Another preferred formula (I) scheme is that wherein X is a hydrogen and W is the (iii) formula of group (Ia) compound of formula: Wherein V is a hydrogen or halogen; R B1-B4Correspondingly as this paper front to R A1-A4Definition; And m is selected from 1,2,3 or 4.
Therefore, in preferred scheme, the present invention relates to the method for preparation formula (IIa) compound: Comprise the intramolecular cyclization step of carrying out twice formula (Ia) compound:
Figure A9980786700223
R wherein A1-A4, V, Y, Z such as preceding definition;
R B1-B4Be selected from hydrogen independently of one another, the alkyl of non-imposed replacement, the thiazolinyl of non-imposed replacement, the alkynyl of non-imposed replacement, the hydroxyl of non-imposed protection, the amino of non-imposed replacement, the alkoxyl group of non-imposed replacement, the alkene oxygen base of non-imposed replacement, the alkynyloxy group of non-imposed replacement, the aryl of non-imposed replacement, the heterocyclic radical of non-imposed replacement, carboxyl, carboxyl ester, amide group, acyl group, acyloxy, sulfydryl, the alkylthio of non-imposed replacement, halogen, nitro, sulfate radical, phosphate radical and cyano group; Or
R B2And R B3Form a key together non-imposedly, and R A1And R A4As above definition or form the carbocyclic ring or the heterocyclic radical of non-imposed replacement with the carbon atom that it connected; Or
R B2And R B3Form the saturated or unsaturated carbocyclic or the heterocyclic radical of non-imposed replacement with the carbon atom that it connected; Or
R B1R B2C-CR B3R B4Form the aryl or the fragrant heterocyclic radical of non-imposed replacement; And
M is selected from 1,2, and 3 or 4.
Another preferred scheme of the present invention provides the midbody compound of formula (Ia) Wherein:
R A1-A4, R B1-B4, V, Y, Z and m such as preceding definition, and non-imposed the ground, (CH that defines in (iii) in formula 2) mIn one or more (CH 2) can be non-imposedly by the radicals R as preceding definition 14Replace.
In another preferred scheme, m is 1 or 2.More preferably, m is 2.
In formula (Ia) with (IIa) in another program of compound, work as R B1R B2C-CR B3R B4When forming aryl or fragrant heterocyclic radical, it can be the benzene or the naphthalene nucleus of a non-imposed replacement, or the fragrant heterocyclic radical of non-imposed replacement such as pyridine, furans, pyrroles or thiophene and its benzene-condensed analogue, for example, quinoline, indoles, cumarone and thionaphthene.Bicyclic heterocyclic radical can connect through benzene or heterocycle.R preferably B1R B2C-CR B3R B4Form the phenyl of non-imposed replacement.Work as R B1R B2C-CR B3R B4Form phenyl when (containing substituting group V), cyclisation can provide as this paper formula recited above (i) group.Substituting group is hydrogen preferably; Hydroxyl; The alkyl of non-imposed replacement; The alkoxyl group of non-imposed replacement; Acyloxy; Carboxyl; Carboxyl ester, this ester methyl preferably wherein, ethyl, propyl group or butyl ester; The amino of non-imposed replacement; Formamido-, wherein its nitrogen-atoms is independently selected from methyl by one or two, ethyl, the alkyl of propyl group or butyl replaces non-imposedly; Or sulfate radical.Most preferably, they are hydrogen, hydroxyl, methoxyl group, oxyethyl group, isopropoxy, methyl, ethyl, propyl group, acetoxyl group or sulfate radical.
In another program, R B1-B4Preferably be independently selected from hydrogen, the alkyl of non-imposed replacement, the hydroxyl of non-imposed protection, the alkoxyl group of non-imposed replacement, the phenyl of non-imposed replacement or acyloxy.In another preferred scheme, R B1Or R B3At least one can be hydrogen.In another program, R B1And R B3All be hydrogen.In another program, R B1-B4In three or four be hydrogen.
In another program, work as R B2And R B3Form a key together, thereby form R B1C=CR B4The time, R B1And R B4Can be independently selected from hydrogen; Hydroxyl; The alkyl of non-imposed replacement; The alkoxyl group of non-imposed replacement; Acyloxy; Carboxyl; Carboxyl ester, this ester methyl preferably wherein, ethyl, propyl group or butyl ester; The amino of non-imposed replacement; Formamido-, wherein its nitrogen-atoms is independently selected from methyl by one or two, ethyl, the alkyl of propyl group or butyl replaces non-imposedly.In particularly preferred form, R A1And R A4In one or both be hydrogen.
Work as R B2And R B3When forming as the carbocyclic ring of preceding definition or heterocyclic radical with the carbon atom that it connected, preferably form 3 to 8-person's cyclic group, preferred 5 to 6-person's cyclic group.Preferably, they form pentamethylene, hexanaphthene, cyclopentenes, tetrahydrobenzene, cyclopentadiene, cyclohexadiene, tetrahydrofuran (THF), dihydrofuran, tetramethyleneimine, pyrroles woods, pyrans, dihydropyrane, tetrahydropyrans or piperidyl.Preferably, R B1And R B4Be hydrogen.
Particularly preferred formula (I) compound has the structure as shown in the formula (Ib):
Figure A9980786700241
R wherein 1-14Be independently selected from hydrogen, the alkyl of non-imposed replacement, the thiazolinyl of non-imposed replacement, the alkynyl of non-imposed replacement; the hydroxyl of non-imposed protection, the amino of non-imposed replacement, the alkoxyl group of non-imposed replacement, the alkene oxygen base of non-imposed replacement; the alkynyloxy group of non-imposed replacement, the aryl of non-imposed replacement, the heterocyclic radical of non-imposed replacement, carboxyl; carboxyl ester, amide group, acyl group, acyloxy; sulfydryl, the alkylthio of non-imposed replacement, halogen; nitro, sulfate radical, phosphate radical and cyano group.Preferred R 1-14Be selected from hydrogen; Hydroxyl; The alkyl of non-imposed replacement; The alkoxyl group of non-imposed replacement; Acyloxy; Carboxyl; Carboxyl ester, this ester methyl preferably wherein, ethyl, propyl group or butyl ester; The amino of non-imposed replacement is as one or dialkyl amido; Amide group, wherein its nitrogen-atoms is independently selected from methyl by one or two, ethyl, the alkyl of propyl group or butyl replaces non-imposedly; Or sulfate radical.Most preferably, R 1-13Be selected from hydrogen; Hydroxyl; The alkyl of non-imposed replacement, as methyl, ethyl or propyl group; The alkoxyl group of non-imposed replacement such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy; Acyloxy such as acetoxyl group; Or sulfate radical, and R 14Preferably hydrogen or hydroxyl.V such as preceding definition, preferably hydrogen, iodine or bromine.
More preferred form of the present invention provides thick many rings of preparation formula (IIb) to contain the method for azole compounds:
Figure A9980786700251
Comprise formula (Ib) compound is carried out cyclisation step twice.
Formula (I), the preferred formula (Ia) or (Ib) intramolecular cyclization of compound form formula (II), and the step of many rings condensed compounds of preferred formula (IIa) or formula (IIb) can be undertaken by the known any suitable means of those skilled in the art.Suitable method is described below, and still, any other method that can implement required cyclisation also forms part of the present invention.Should be appreciated that group V, W, X, Y, Z, R A1-A4, R B1-B4, and R 1-4Should be the form of not disturbing cyclization process.
When V represents hydrogen atom, oxidisability intramolecular cyclization method, as Black etc., Tetrahedron Lett., 1989,30,5807 and Kita etc., Chem.Commun., described in 1996,1481, can be used to implement cyclisation.
In addition, when V is halogen atom, intramolecular cyclization can through with Antonio etc., Can.J.Chem., 1994,72,15 and Moody etc., Tetrahedron Lett., the similar mode of the method described in 1995,36,9501 produces suitable group and carries out.
When V was halogen, the other method that is used for formula (I) compound molecule intramolecular cyclization comprised Pd[O]-mediation cyclisation.Intramolecularly Pd[O]-alkylene (intramolecularly Heck reaction) of catalytic Organohalogen compounds is known for those skilled in the art, and the combination of any appropriate of reagent that can be by zeroth order palladium (Pd[O]) can be provided is carried out.
Be used to implement Pd[O]-the suitable agent combination of catalytic cyclisation is for example in Burwood etc., Tetrahedron Lett., 1995,36,9503; Desarbe etc., Heterocycles, 1995,41,1987; Harayoma etc., Chem.Pharm.Bull., 1997,45,1723; With Grigg etc., Tetrahedron, 1995,50,359.
Therefore, in a scheme of the present invention, the Pd[O of formula (I)]-catalytic cyclisation can pass through Pd[II] reagent and " part " combination and produce Pd[O on the spot] carry out, and further be provided for Pd[O] alkali of catalyst regeneration.
Suitable Pd[II]/Pd[O] example of reagent includes, but are not limited to: Pd (OAc) 2, PdCl 2(CH 3CN) 2, PdCl 2(PPh 3) 2, Pd (C 6H 5CN) 2Cl 2, Pd (dibenzalacetone) 3
Provide the suitable example of " part " of reagent to include, but are not limited to: PPh 3, P (o-tolyl) 31,3-two [diphenylphosphino] propane and 1,3-two [diphenylphosphino] ethane.
Be used for from Pd[O]-Pd[II that forms during the catalytic cyclisation] regeneration Pd[O] suitable alkali include, but are not limited to: alkylamine, as triethylamine and diisopropylethylamine; Acetate is as sodium-acetate and Potassium ethanoate; Carbonate such as salt of wormwood, yellow soda ash, silver carbonate; With oxyhydroxide such as sodium hydroxide and potassium hydroxide.
Compound is processed and carry out dicycloization when formula (Ia) or (Ib), form formula (Ia) or (IIb) during compound, cyclisation can be passed through group, the cyclization process of aforesaid oxidisability or Pd-mediation is realized, each cyclisation can be with identical, and similar or different modes is carried out.
Therefore, in a scheme, two cyclisation can be carried out with any order continuously, and can use different reagent and condition non-imposedly, and are for example aforesaid.Non-imposed ground carries out after a cyclisation, and the monocycle product can be separated, handles under appropriate condition then and carries out the intramolecular cyclization second time.As another kind of form, the carrying out that " dicycloization " can " treat different things alike " preferably carries out under single cover reaction conditions.
As more preferred form, make formula (Ia), the compound of preferred (Ib) is at Pd[O]-carry out " dicycloization " under the catalytic condition to form formula (IIa), preferred (IIb) compound.
As going back more preferred form, twice cyclisation all carried out in " treating different things alike " mode under single cover reaction conditions.
Formula (I), (Ia) and (Ib) compound can be by the known standard technology that carries out the replacement of pyrroles's core carbon atom of those skilled in the art, prepare from pyrroles's core, for example by electrophilic aromatic substitution or halogenated pyrrole nuclear, and use stannane, and boric acid or zn cpds such as aryl stannane, aryl boric acid and aryl zn cpds pass through Stile, Suzuki, or Negishi cross-coupling reaction and replacing.The replacement of N-atom can be undertaken by standard technology.
Without any limited significance, a suitable method is described in diagram 1, and this diagram is used to illustrate the suitable method of substituted azole nuclear.
Should be appreciated that, by being used for introducing 1-to pyrroles's core, 2-, use suitable reagent in the step of 4-replacement type, for example, be used for step (d), (e) and (f) contain phenyl reagent, wherein phenyl moiety further is substituted as previously mentioned, and replacement type and substituting group can be introduced into to form can carry out the intermediate of cyclization process, and forms the compound of corresponding cyclisation.
Figure A9980786700281
Diagram 1 diagram 1: reagent and condition: (a) Cl 3CCOCl (1 molar equivalent), Et 2O, 35 ℃, 1 hour (80%); (b) I 2(1 molar equivalent), AgO 2CCF 3(1 molar equivalent), CHCl 3, 18 ℃, 1 hour (82%); (c) K 2CO 3(2M H 2O), DMSO, 18 ℃, 32 hours (92%); (d) (i) (COCl) 2(1.1 molar equivalent), DMF (catalytic amount), CH 2Cl 2, 18 ℃, 2 hours; (ii) adjacent bromophenol (1 molar equivalent), DMAP (catalytic amount), CH 2Cl 2, 18 ℃, 1 hour (92%); (e) K 2CO 3(1.14 molar equivalent), Bu 4NCl (0.1 molar equivalent), DMF, 80 ℃, 2 hours (90%); (f) PhZnCl (1.3 molar equivalent), PdCl 2(PPh 3) 2(0.05 molar equivalent), THF/DMF, 18 ℃, 1 hour (95%); (g) Pd (OAc) 2(0.5 molar equivalent), PPh 3(1 equivalent), NaOAc (4 equivalent), DMF, 130 ℃, 6 hours (16%); (h) TsCl (2.4 molar equivalent), KOH (2.4 molar equivalent), Et 2O, 0-18 ℃, 2 hours (98%).
When dispensable pair of key exists, as formula (II) compound that contains formula (I) part can perhaps, be introduced this pair key by mix corresponding two key in its precursor by the dehydrogenation of cyclisation product suc as formula in (IIb) compound.Suitable method is those skilled in the art known (referring to for example, Advanced Organic Chemistry, Reactions.Mechanisms.andStructure, Jerry March, the third edition, Wiley Interscience).A kind of suitable method comprises formula (IIb) compound of handling cyclisation with DDQ (2,3-two chloro-5,6-dicyano-1,4-benzoquinones).For example, Lamellarin T diisopropyl ether (compound 37 in the table 2) can by with DDQ in the exsiccant chloroform, handle and be converted into Lamellarin W Di Iso Propyl Ether (compound 11 in the table 1) (referring to the embodiment among the WO98/50365 11) in 60-65 ℃.
WO97/01336 (its whole contents is mixed this paper with the form of reference) has described a class and has had the inhibition of anti-multiple medicines thing tolerance type tumour and/or the compound of cellular cytoxicity activity.
Therefore, further aspect of the present invention provides methods of treatment, comprises the animal to needs, comprises that the people uses general formula (II) compound of method as described herein preparation of significant quantity as activeconstituents.
Term used herein " significant quantity " refers to when according to required dose mode administration, and the amount of the compound of required therapeutic activity is provided.Dosed administration can divide, hour, day, week, month or year the interval take place, or surmount these cycles any one carry out continuously.Proper dosage at the every approximately kg body weight of every dosage 0.1ng to the scope of every kg body weight 1g.Preferably, dosage is in the scope of the every kg body weight 1 μ g of every dosage to every kg body weight 1g.More preferably, dosage is in the scope of the every kg body weight of every dosage 1mg to every kg body weight 1g.Suitably, dosage is in the scope of the every kg body weight of every dosage 1mg to every kg body weight 500mg, as 1mg to 250mg or 1mg to 100mg.
In preferred scheme, methods of treatment relates to the tumour for the treatment of the tolerance of multiple medicines thing.
In another program, methods of treatment relates to improves the anti-tumor chemotherapeutic effect that the tolerance of multiple medicines thing influences medicine.
In another preferred scheme, methods of treatment is the method for cell death inducing.More preferably, methods of treatment is to the apoptotic method of multiple medicines thing tolerance cell induction.
In another program, methods of treatment relates to the adjusting immunologic function.
Activeconstituents can be by single dose or a series of dosed administration.Can be at activeconstituents by in the independent administration, preferably with composition, the form of preferred pharmaceutical compositions exists.
The present invention also relates in one aspect to and comprises general formula prepared according to the methods of the invention (II) compound and pharmaceutical carrier, vehicle or thinner composition together.
Carrier must be pharmaceutically " acceptable ", promptly can hold altogether with other compositions in the composition, and does not injure main body.Composition comprise be suitable for oral, rectum, in the nose, local (comprising in the cheek and the hypogloeeis), the composition of intravaginal or parenteral (comprise subcutaneous, intramuscular, intravenously and intradermal) administration.Said composition can exist with unit dosage form easily, and can be by the known any method preparation of pharmaceutical industry.These class methods comprise makes activeconstituents and the carrier blended step of being made up of one or more ancillary components.In general, composition mixes nearly by making activeconstituents and liquid vehicle or very thin solid carrier or they both being all even, if desired, and then with product shaping.
The present composition that is suitable for oral administration can be with the capsule of isolating unit as the activeconstituents that contains predetermined amount separately, anther sac or tablet; With pulvis or granule; With solution in the aqueous solution or non-aqueous solution or suspension; Or exist with oil-in-water emulsion or oily water conservation emulsion.Activeconstituents also can be with pill, and electuary or paste exist.
Tablet can pass through compressing tablet or pressing mold, and non-imposed ground in addition one or more ancillary components is made.The tablet of compacting can by in machine suitably with activeconstituents with free-pouring form such as powder or particle, non-imposedly with tackiness agent (inert diluent for example, sanitas, disintegrating agent (Explotab for example, cross-linked polyvinylpyrrolidone, croscarmellose sodium), tensio-active agent or dispersant, compressing tablet and preparing.Molded tablet can will be made with the mixture pressing mold of the wetting powdered compounds of inert liquid diluent by in suitable machine.This tablet can non-imposed ground dressing or indentation, and by slowly-releasing or the controlled release of preparation so that activeconstituents to be provided, wherein uses with different ratios, and for example Vltra tears provides required releasing pattern.Tablet can discharge it non-imposedly with the casing parcel in intestines rather than in the stomach.
Be suitable for that topical drug delivery composition is included in the seasoning base in mouth, be generally the lozenge that comprises activeconstituents in sucrose and gum arabic or the tragacanth gum; At inert base such as gelatin or glycerine, or comprise the pastille of activeconstituents in sucrose and the gum arabic; With the mouth wash shua that in suitable liquid vehicle, comprises activeconstituents.
The composition that is used for drop rectum with drug can comprise to have suitable matrix, and for example the suppository of theobroma oil exists.
The composition that is suitable for intravaginal administration can be to contain except that activeconstituents the vaginal suppository of carrier as known in the art, stopper, ointment, gel, paste, foam or spray agent existence.
The composition that is suitable for administered parenterally comprises the isotonic sterile injection liquid of water or non-water, and it can contain antioxidant, buffer reagent, sterilant and the isoosmotic solute of blood that makes composition and acceptor; The water and the non-water sterile suspensions that can comprise suspension agent and thickening material.Said composition may reside in single dose or multiple doses sealed vessel, for example in ampoule and the bottle, and can store under freeze-dried (freeze-drying) condition, only need add sterile liquid carrier, for example water for injection before use.On-the-spot injection solution and suspension can be from the sterile powders of aforesaid kind, granule and tablet preparation.
Preferred units dosage composition is to contain per daily dose or unit as mentioned above, day sub-doses, or the composition of active components of its suitable part.
Should be understood that, except the activeconstituents that last mask body is mentioned, composition of the present invention can comprise the common medicament in this area that other are relevant with the types of compositions of being discussed, for example, being suitable for liquid preparations for oral administration can comprise such as tackiness agent, sweeting agent, thickening material, seasonings, disintegrating agent, Drug coating, sanitas, the medicament of lubricant and/or delay agent.Suitable sweeting agent comprises sucrose, lactose, glucose, aspartame or asccharin.Suitable disintegrants comprises W-Gum, methylcellulose gum, Polyvinylpyrolidone (PVP), xanthan gum, wilkinite, alginic acid or agar.Suitable seasonings comprises spearmint oil, wintergreen oil, cherry, orange or raspberry seasonings.Suitable Drug coating comprises polymkeric substance or multipolymer, wax, Fatty Alcohol(C12-C14 and C12-C18), zein, lac or the gluten of vinylformic acid and/or methylacrylic acid and/or its ester.Suitable sanitas comprises Sodium Benzoate, vitamin-E, alpha-tocopherol, xitix, methyl p-hydroxybenzoate, propylparaben or sodium bisulfite.Examples of suitable lubricants comprises Magnesium Stearate, stearic acid, sodium oleate, sodium-chlor or talcum.Suitable delay agent comprises monostearin or Stearic diglyceride.
What the present invention also provided general formula (II) compound prepared according to the methods of the invention is used for the treatment of purposes aspect animal or human that this needs are arranged medical in production.
The present invention relates on the other hand and comprises the medicament that general formula prepared according to the methods of the invention (II) compound is used for the treatment of the animal or human that this needs are arranged.
In first scheme, medicament is used for the treatment of multiple medicines thing tolerance tumour.
In another program, medicament be used for multiple medicines thing tolerance cell induction apoptotic.
Also in the scheme, medicament is the anti-tumor chemotherapeutic effect that is used to improve the medicine of multiple medicines thing tolerance influence.
Another program is the medicament that is used to regulate immunologic function.
The present invention also relates in one aspect to the purposes that general formula (I) compound is used for the treatment of the animal or human that this needs are arranged.Preferably, general formula (I) compound prepares by foregoing method.
In preferred scheme, this purposes is a treatment multiple medicines thing tolerance tumour.
In another program, purposes is to improve the anti-tumor chemotherapeutic effect of the medicine of multiple medicines thing tolerance influence.
Also a scheme is to be used to regulate immunologic function.
Preferably, meaning without limits can be described in table 1 and the table 2 below through the example of the compound of intermediate preparation of the present invention.Following table reaches hereinafter, and " Commpound " represents compound, and " Lamellarin " is sheet spiral shell element, and " Sulfate " is vitriol, and " acctate, diacctate, triacetate " is respectively acetate, diacetate, triacetate.Table 1
Figure A9980786700331
??Compound ??R 1 ??R 2 ??R 3 ??R4 ??R 5 ??R 6 ?R 7 ??R 8??R 9 ?R 10 ?R 11 ??R 12??R 13
??1 ??H ??H ??H ??H ??H ?H ??H ?H ?H ??H
??2(Lamellarin?B) ??OMe ??OMe ??OMe ??H ??OMe ?OH ??H ?OMe ?OH ??H
??3(Lamellarin?D) ??H ??OH ??OMe ??H ??OMe ?OH ??H ?OMe ?OH ??H
??4(Lamellarin?D- ????triacetate) ??H ??OAc ??OMe ??H ??OMe ?OAc ??H ?OMe ?OAc ??H
??5(Lamellarin?M) ??OH ??OMe ??OMe ??H ??OMe ?OH ??H ?OMe ?OH ??H
??6(Lamellarin?M- ????triacetate) ??OAc ??OMe ??OMe ??H ??OMe ?OAc ??H ?OMe ?OAc ??H
??Compound ??R 1 ?R 2 ?R 3 ??R4 ??R 5 ?R 6 ?R 7 ??R 8??R 9 ??R 10 ??R 11 ??R 12??R 13
??7(Lamellarin?N) ??H ?OH ?OMe ??H ?OMe ?OH ??H ??OH ??OMe ??H
??8(Lamellarin?N- ????triacetate) ??H ?OAc ?OMe ??H ?OMe ?OAc ??H ??OAc ??OMe ??H
??9(Lamellarin?W) ??OMe ?OMe ?OMe ??H ?OMe ?OH ??H ??OH ??OMe ??H
??10(Lamellarin?X) ??OH ?OMe ?OMe ??H ?OMe ?OH ??H ??OH ??OMe ??H
??11 ??OMe ?OMe ?OMe ??H ?OMe ?O iPr ??H ??O iPr ??OMe ??H
Table 2
Figure A9980786700351
??Compound ??R 1 ??R 2 ?R 3 ??R 4??R 5 ?R 6 ?R 7 ?R 8?R 9 ?R 10 ?R 11 ??R 12??R 13 ??R 14
?12(Lamellarin?A) ??OMe ??OMe ?OMe ??H ?OMe ?OH ?H ?OMe ?OH ??H ??OH
?13(Lamellarin?C) ??OMe ??OMe ?OMe ??H ?OMe ?OH ?H ?OMe ?OH ??H ??H
?14(Lamellarin?E) ??OH ??OMe ?OMe ??H ?OMe ?OH ?H ?OH ?OMe ??H ??H
?15(Lamellarin?F) ??OH ??OMe ?OMe ??H ?OMe ?OH ?H ?OMe ?OMe ??H ??H
?16(Lamellarin?G) ??H ??OH ?OMe ??H ?OH ?OMe ?H ?OH ?OMe ??H ??H
?17(Lamellarin?H) ??H ??OH ?OH ??H ?OH ?OH ?H ?OH ?OH ??H ??H
??Compound ??R 1 ??R 2 ??R 3 ??R 4??R 5 ?R 6 ?R 7 ??R 8??R 9 ?R 10 ??R 11 ??R 12??R 13 ??R 14
?18(Lamellarin?I) ??OMe ??OMe ??OMe ??H ?OMe ?OH ??H ?OMe ??OMe ??H ??H
?19(Lamellarin?I- ????acetate) ??OMe ??OMe ??OMe ??H ?OMe ?OAc ??H ?OMe ??OMe ??H ??H
?20(Lamellarin?J) ??H ??OH ??OMe ??H ?OMe ?OH ??H ?OMe ??OMe ??H ??H
?21(Lamellarin?K) ??OH ??OMe ??OMe ??H ?OMe ?OH ??H ?OMe ??OH ??H ??H
?22(Lamellarin?K- ????triacetate) ??OAc ??OMe ??OMe ??H ?OMe ?OAc ??H ?OMe ??OAc ??H ??H
?23(Lamellarin?L) ??H ??OH ??OMe ??H ?OMe ?OH ??H ?OH ??OMe ??H ??H
?24?(Lamellarin?L- ????triacetate) ??H ??OAc ??OMe ??H ?OMe ?OAc ??H ?OAc ??OMe ??H ??H
?25(Lamellarin?S) ??H ??OH ??OMe ??H ?OH ?OH ??H ?OH ??OH ??H ??H
?26(Lamellarin?T) ??OMe ??OMe ??OMe ??H ?OMe ?OH ??H ?OH ??OMe ??H ??H
??Compound ??R 1 ??R 2 ??R 3 ??R 4??R 5 ??R 6 ??R 7 ??R 8??R 9 ??R 10 ??R 11 ??R 12??R 13 ??R 14
??27(Lamellarin ??T20-sulfate) ??OMe ?OMe ?OMe ??H ?OMe ?OSO 3??Na ??H ??OMe ??OH ??H ??H
??28 ??H ?OMe ?OMe ??H ?H ??H ??H ??H ??H ??H ??H
??29(Lamellarin?U) ??H ?OMe ?OMe ??H ?OMe ?OH ??H ??OH ??OMe ??H ??H
??30(Lamellarin ??U20-sulfate) ??H ?OMe ?OMe ??H ?OMe ?OSO 3??Na ??H ??OH ??OMe ??H ??H
??31(Lamellarin?V) ??OMe ?OMe ?OMe ??H ?OMe ?OH ??H ??OH ??OMe ??H ??OH
??32?(Lamellarin ??V20-sulfate) ??OMe ?OMe ?OMe ??H ?OMe ?OSO 3??Na ??H ??OH ??OMe ??H ??OH
??33(Lamellarin ??Y20-sulfate) ??H ?OMe ?OH ??H ?OMe ?OSO 3??Na ??H ??OH ??OMe ??H ??H
??34 ??H ?OMe ?OMe ??H ?OMe ?O iPr ??H ??OMe ??O iPr ??H ??H
??35 ??H ?OMe ?OMe ??H ?OMe ?OH ?H ??OMe ??OH ??H ??H
?Compound ?????R 1 ??R 2 ??R 3 ??R 4??R 5 ??R 6 ??R 7 ??R 8??R 9 ??R 10 ??R 11 ??R 12??R 13 ???R 14
???36 ????O iPr ?OMe ?OMe ??H ?OMe ?O iPr ??H ?OMe ?O iPr ????H ????H
???37 ????OMe ?OMe ?OMe ??H ?OMe ?O iPr ??H ?O iPr ?OMe ????H ????H
???38 ????H ?OMe ?OMe ??H ?OMe ?O iPr ??H ?O iPr ?OMe ????H ????H
???39(Lamellarin?T ??????diacetate) ????OMe ?OMe ?OMe ??H ?OMe ?OAc ??H ?OAc ?OMe ????H ????H
The present invention describes with reference now to the following example.But, should be appreciated that the general remark of these and front specification sheets is contradiction not.Hereinafter " broad " or " broadened " expression " wide " or " broadening ", " lit " represent literature value." Found " is measured value, and " requires " is theoretical value, and " Mass Spectrum " is mass spectrum.
Embodiment
Embodiment 12-(tribromo-acetyl base) pyrroles
According to Bailey etc., Org.Synth., 1971,100 method, from the pyrroles (12.5g, 186mmol) and trichoroacetic chloride (36.5g, 200mmol) preparation 2-(tribromo-acetyl base) pyrroles.In this method, obtain title compound with the paste solid form, m.p.73-74 ℃ (lit.m.p.73-75 ℃). 1H n.m.r.d9.30, broad s, 1H; 7.39, m, 1H; 7.17, m, 1H; 6.40, dt, J3.9and2.4Hz, 1H. (referring to J.Org.Chem., 1972,37,3618; 1993,58,7245) .4-iodo-2-(tribromo-acetyl base) pyrroles
According to Belanger, Tetrahedron Lett., 1979,2505 method prepares title compound from 2-(tribromo-acetyl base) pyrroles.Under magnetic agitation; with iodine (12.0g, 47.2mmol) with 0.17 hour in batches (every crowd of about 1g) add trifluoroacetic acid silver (11.0g, 49.8mmol) and 2-(tribromo-acetyl base) pyrroles (10.0g; 47.1mmol) mixture in dry chloroform (70ml), keep 0 ℃ (ice bath).After adding, make reaction mixture be warmed to 18 ℃, and under this temperature restir 2 hours.Filter the suspension that produces with agglomerating glass funnel (No.3 porosity), filtrate is used Na 2S 2O 5(2 * 80ml) washings, dry (sal epsom) then filters and concentrating under reduced pressure for (1 * 80ml 5%w/v aqueous solution) and water.The solid residue of gained hexane/ether (50ml 4: the 1v/v mixture) handle, the suspension of generation stirred 5 hours at 18 ℃, leached solid then, provided title compound (13.1g, 82%) paste solid,
M.p.129-130 ℃ (lit.m.p.128-130 ℃). 1H n.m.r.d 9.45, broad s, 1H; 7.44, dd, J2.6and1.3Hz, 1H; 7.19, dd, J 2.6and1.3Hz, 1H.4-iodol-2-carboxylic acid
Salt of wormwood (the 100ml 2M aqueous solution) is added 4-iodo-2-(tribromo-acetyl base) pyrroles, and (8.5g, in DMSO 2.5mmol) (30ml) solution, the mixture of generation stirred 3 hours at 18 ℃, water (200ml) dilution then.(2 * 100ml) washings are acidified to pH3 by dripping hydrochloric acid (the 2M aqueous solution) to the solution of gained then with ethyl acetate.(with the organic moiety drying (sal epsom) that merges, filter and concentrating under reduced pressure, provides title compound (8) (5.51g, 92%) white solid, m.p.200 ℃ of (actual measurement: M by 3 * 100ml) extractions with ethyl acetate for the soup compound that produces +-, 236.9285.C 5H 4INO 2Calculated value M +-, 236.9287)
n Max(KBr) 3287,3129,3035,1703,1544,1430,1300,1212,1122cm -1. 1H n.m.r.[300 MHz, 3: 1 (CD 3) 2SO/CDCl 3] d 11.98, broad s, 1H; 6.98, t, J1.5Hz, 1H; 6.76, wide s, 1H (not observing the resonance of N-H). 13C n.m.r.[75.5MHz, 3: 1 (CD 3) 2SO/CDCl 3] d 159.0 (C), 126.0 (CH), 123.3 (C), 118.8 (CH), 59.0 (C) .Mass spectrumm/z, 237 (100%) (M +-); 219 (87) [(M-H 2O) +-] .4-iodol-2-carboxylic acid 2-bromophenyl ester
Under magnetic agitation, (203ml 2.32mmol) adds 4-iodol-2-carboxylic acid (8) (500mg, 2.11mmol) suspension in the dry methylene chloride (15.0ml) that contains DMF (1) with oxalyl chloride.The solution that produces 18 ℃ stir 2 hours after, with its under magnetic agitation, add the o-bromophenol (363mg, 2.11mmol), triethylamine (660ml, 4.73mmol) and the solution of 4-(N, N-dimethylamino) pyridine (DMAP, several crystal) in methylene dichloride (10ml).After 1 hour, reaction mixture is concentrated on the silica gel (5g), and resistates is carried out flash chromatography (silica gel, 3: 1 hexane/ether wash-outs).With suitable fraction (R f0.2) concentrate, provide the white crystalline solid of title compound (761mg, 92%), m.p.126-127 ℃
(Found:C, 33.9; H, 1.7; Br, 20.4; I, 32.4; N, 4.0.C 11H 7BrINO 2Requires C, 33.7; H, 1.8; Br, 20.4; I, 32.4; N, 3.6%) .n Max(KBr) 3383,2969,1709,1580,1541,1472,1444,1377,1312,1218,1169,1133,1043 cm -1. 1H n.m.r.d 9.57, broad s, 1H; 7.65, dd, J8.1and1.5Hz, 1H; 7.37, td, J8.1and1.5Hz, 1H; 7.27, m, 2H; 7.18, td, J8.1and1.5Hz, 1H; 7.08, m, 1H. 13C n.m.r.d 158.0 (C), 148.3 (C), 134.0 (CH), 129.8 (CH), 129.1 (CH), 128.1 (CH), 124.4 (CH), 124.3 (CH), 123.6 (C), 116.9 (C), 62.9 (C) .Mass spectrum m/z, 393 (24%) 391 (22) (M +-); 220 (100) [(M-C 6H 4BrO) +-] .4-toluenesulphonic acids 2-(2-bromophenyl) ethyl ester (13)
Under magnetic agitation, with 2-bromobenzene ethanol (5.00g, 24.9mmol, ex ALDRICH) and 4-toluene sulfonyl chloride (11.20g, 59.7mmol) ether (50ml) solution be cooled to 0 ℃ (ice bath), use Powdered potassium hydroxide (3.2g, 2.4 molar equivalents) to handle then.The reaction mixture of gained is warmed to 18 ℃, stirs 2.0 hours water (100ml) dilution then under this temperature.(1 * 100ml) washing, dry (sal epsom) then filters and concentrating under reduced pressure the organic phase water of telling, and provides white solid.Because this material contains remaining 4-toluene sulfonyl chloride, so it is dissolved in pyridine (75ml), the solution of generation stirred 0.16 hour at 18 ℃, and water (500ml) dilutes then, and (1 * 500ml) extracts with ether.The organic phase of telling is used sodium bicarbonate (1 * 250ml 0.5M aqueous solution) washing, then dry (sal epsom) then with hydrochloric acid (1 * 250ml 5M aqueous solution) washing, filter and concentrating under reduced pressure, provide the white crystalline material of title compound (8.66g, 98%), m.p.39-39.5 ℃
(Found:C, 50.9; H, 4.2; Br, 22.6; S, 8.8.C 15H 15BrO 3S requires C, 50.7; H, 4.3; Br, 22.5; S, 9.0%) .n Max(KBr) 1356,1177,1021,980,962,895,812,769,752,665,557cm -1. 1H n.m.r.d7.68, d, J8.3Hz, 2H; 7.45, d, J7.7Hz, 1H; 7.27, d, J8.3Hz, 2H; 7.17, m, 2H; 7.07, m, 1H; 4.25, t, J7.0Hz, 2H; 3.09, t, J7.0Hz, 2H; 2.43, s, 3H. 13C n.m.r.d144.5 (C), 135.3 (C), 132.7 (CH), 132.8 (C), 131.3 (CH), 129.7 (CH), 128.5 (CH), 127.6 (CH), 127.4 (CH), 124.2 (C), 68.6 (CH 2), 35.5 (CH 2), 21.5 (CH 3) .Mass spectrum m/z 356 (0.7%) 354 (0.7) (M +-); 184 (98) 182 (100) [M-H 3CC 6H 4SO 3H) +-]; 171 (49) 169 (51); 155 (45); 103 (32); 91 (80) (C 7H 7+) .1-[2 '-(2 "-bromophenyl) ethyl]-4-iodol-2-carboxylic acid 2-bromophenyl ester
With compound (13) (700mg, 1.97mmol), etamon chloride (30mg, 0.18mmol) and salt of wormwood (278mg, 2.0mmol) (soup compound of generation stirred 2 hours at 80 ℃ for 700mg, the 1.79mmol) solution in exsiccant DMF (30ml) to add compound (11).The reaction mixture that cooled off dilutes with ethyl acetate (150ml), and water (3 * 150ml) washings.With the organic phase drying of telling (sal epsom), filter and concentrating under reduced pressure then.The solid residue of gained carries out flash chromatography (silica gel, 4: 1 hexane/ether wash-outs), concentrates required fraction (R f0.5,3: 1 hexane/ether wash-outs) and provide the white crystalline solid of title compound (14) (920mg, 89%), m.p.122-123 ℃
(Found:C, 39.5; H, 2.1; Br, 27.6; I, 22.1; N, 2.3.C 19H 14Br 2INO 2Requires C, 39.7; H, 2.5; Br, 27.8; I, 22.1; N, 2.4%) .n Max(KBr) 2949,1716,1517,1468,1438,1411,1374,1326,1232,1216,1191,1055,1028 cm -1. 1H n.m.r.d 7.65, dd, J7.8and1.8Hz, 1H; 7.55, dd, J7.8and1.8Hz, 1H; 7.37, m, 2H; 7.28-7.04, m, 5H; 6.70, d, J2.1Hz, 1H; 4.55, t, J7.5Hz, 2H; 3.20, t, J7.5Hz, 2H. 13C n.m.r.d 157.0 (C), 147.8 (C), 136.9 (C), 134.5 (CH), 133.3 (CH), 132.7 (CH), 131.2 (CH), 128.6 (CH), 128.4 (CH), 127.6 (CH), 127.3 (CH), 126.7 (CH), 124.4 (C), 124.0 (CH), 122.0 (C), 116.6 (C), 59.6 (C), 49.0 (CH 2), 38.0 (CH 2) .Mass spectrumm/z 577 (1%) 575 (2) 573 (1) (M +-); 496 (10) 494 (11) [(M-Br -) +]; 404 (98) 402 (100) [(M-C 6H 4BrO -) +] .1-[2 '-(2 "-bromophenyl) ethyl]-4 phenylpyrroles-2-carboxylic acid 2-bromophenyl ester (4)
Under magnetic agitation, in 2 minutes with the phenyl zinc chloride [by with Zinc Chloride Anhydrous (540mg, 3.96mmol) adding phenyl lithium (hexanaphthene/diethyl ether solution of 2.0ml 1.8M, 3.6mmol) THF (4.0ml) solution and prepare] be added drop-wise to compound (14) (1.75g, 3.04mmol) and Pd (PPh 3) 2Cl 2(106mg is in DMF 0.152mmol) (15ml) solution.Continue to stir 1 hour at 18 ℃, then reaction mixture is transferred in the separating funnel, dilute, and wash, water (2 * 100ml) washings then with ammonium chloride (100ml saturated aqueous solution) with ethyl acetate (100ml).With the organic phase drying of telling (sal epsom), filter and concentrating under reduced pressure, provide light yellow oil, it is carried out flash chromatography (silica gel, 2: 1 hexanes/ch wash-outs).Concentrate required fraction (R f0.5) provide title compound (1.52g, 95%) microcrystalline solids, m.p.90-92 ℃
(Found:C, 57.1; H, 3.4; Br, 30.7; N, 2.5.C 25H 19Br 2NO 2Requires C, 57.2; H, 3.7; Br, 30.4; N, 2.7%) .n Max(KBr) 2958,2930,1718,1603,1580,1562,1472,1397,1215,1196,1066,1024 cm -1. 1H n.m.r.d 7.70, dd, J8.0and1.5Hz, 1H; 7.60-7.00, m, 14H; 4.63, t, J6.9Hz, 2H; 3.32, t, J6.9Hz, 2H. 13C n.m.r. (75.5MHz, CDCl 3) d 158.4 (C), 148.3 (C), 137.5 (C), 134.2 (C), 133.5 (CH), 132.9 (C), 131.5 (CH), 128.9 (CH), 128.6 (3) (CH), 128.6 (1) (CH), 127.8 (CH), 127.4 (CH), 127.3 (CH), 126.5 (CH), 125.4 (CH), 124.8 (C), 124.6 (C), 124.4 (CH), 120.9 (C), 117.5 (CH), 116.9 (C), 49.3 (CH 2), 38.2 (CH 2) .Mass spectrum m/z527 (3%) 525 (6) 523 (3) (M +-); 446 (12) 444 (11) [(M-Br) +354 (100) 352 (96) [(M-C 6H 4BrO -) +] .14-phenyl-8,9-dihydro-6H-[1] chromene [4 ', 3 ': 4,5] pyrrolo-[2,1-a] isoquinoline 99.9-6-ketone also
Under magnetic agitation, with Pd (OAc) 2(32mg, 0.143mmol) be added in compound (4) in the Schlenk pipe (148mg, 0.282mmol), NaOAc (92.7mg, 1.13mmol) and PPh 3(74.0mg is in DMF 0.282mmol) (2ml) solution.The mixture that produces is evacuated (1.0mmHg), and uses N 2(gas) recharges (removing dissolved oxygen) 3 times, heats 6 hours in 135 ℃ in nitrogen atmosphere then.The refrigerative reaction mixture dilutes with ether (25ml), and (dry (sal epsom) filters and is concentrated on the silica gel (2g) for 2 * 20ml) washings, water (20ml) washing then with salt solution.Resistates carries out flash chromatography (silica gel, 1: 2,1: 1,2: 1 dichloromethane/hexane wash-outs then), the fraction (R that concentrating under reduced pressure is required f0.3,2: 1 dichloromethane/hexane wash-outs) and provide title compound (16mg, 16%) oyster white crystallite,
M.p.259-260 ℃ of (Found:M +-, 363.1257.C 25H 17NO 2Requires M +-, 363.1259) and .n Max(KBr) 2925,2853,1708,1449,1420,1396,1339,1281,1241,1198,1151,1133,1106,1085,1047 cm -1. 1H n.m.r.d 7.58-7.55, m, 2H; 7.51-7.50, m, 2H; 7.40, dd, J7.5and0.9Hz, 1H; 7.32-7.18, m, 4H; 7.10, dd, J7.8and1.2Hz, 1H; 7.01-6.97, m, 3H; 4.88, t, J6.9Hz, 2H; 3.21, t, J6.9Hz, 2H. 13C n.m.r.d 155.3 (C), 151.2 (C), 135.6 (C), 135.3 (C), 133.8 (C), 130.7 (CH), 129.4 (CH), 128.3 (CH), 128.1 (CH), 127.5 (C), 127.4 (CH), 126.9 (CH), 125.7 (CH), 123.7 (CH), 123.3 (CH), 118.2 (C), 117.5 (C), 117.1 (CH), 42.3 (CH 2), 29.3 (CH 2) (fuzzy or three peaks of eclipsed), Mass spectrum m/z 363 (100%) (M +-) .5,6-dihydro-1-phenylpyrrole also [2,1-a] isoquinoline 99.9-3-carboxylic acid 2 '-bromophenyl ester (16) and bromine 2 '-(5 ", 6 "-dihydro-1 "-phenylpyrrole also [2 ", 1 "-a] isoquinoline 99.9-3 "-carboxyl) phenyl two (triphenyl phosphines) close palladium (17)
With Pd (OAc) 2(197mg, 0.88mmol) add compound (4) (230mg, 0.438mmol), NaOAc (80mg, 0.975mmol) and PPh 3(460mg is in DMF 1.75mmol) (20ml) solution.The solution that produces is evacuated (1.0mmHg), and uses N 2(gas) recharges 3 times to remove dissolved oxygen, heats 19 hours in 110 ℃ in nitrogen atmosphere then.The refrigerative reaction mixture dilutes with ether (25ml), and (2 * 20ml) washings, (1 * 20ml) washs water then with salt solution.The organic phase of telling is dried in (sal epsom), and filtration and concentrating under reduced pressure are to silica gel (2g).Resistates carries out flash chromatography (silica gel, 1: 21: 1 dichloromethane/hexane then, then 4: 1 dichloromethane/ethyl acetate wash-outs), provides fraction A and B.
Concentrate fraction A (R f0.6,2: 1 dichloromethane/hexane wash-outs) and provide the cream-coloured crystalline material of compound (16) (34mg, 17%), m.p.130-131 ℃ of (Found:M +-, 443.0529.C 25H 1879BrNO 2Requires M +-, 443.0521) and .n Max(KBr) 2950,1710,1471,1439,1418,1240,1212,1176,1046cm -1. 1H n.m.r.d 7.57, dd, J8.1and1.5Hz, 1H; 7.45-7.05, m, 12H; 6.95, br t, J8.1Hz, 1H; 4.57, t, J6.3Hz, 2H; 3.05, t, J6.3Hz, 2H. 13C n.m.r.d 158.5 (C), 148.1 (C), 136.1 (C), 133.4 (C), 133.3 (CH), 132.9 (C), 129.1 (CH), 128.6 (C), 128.4 (CH), 128.1 (C), 127.9 (CH), 127.7 (CH), 127.1 (CH), 126.9 (CH), 126.7 (CH), 125.5 (CH), 124.2 (CH), 123.5 (C), 121.3 (CH), 119.4 (C), 116.7 (C), 42.4 (CH 2), 29.5 (CH 2) .Mass spectrumm/z 445 (10%) 443 (9) (M +-); 272 (100) [(M-C 6H 4BrO -) +].
Concentrate fraction B (R f0.1,2: 1 methylene dichloride wash-outs) and provide the cream-coloured crystalline material of compound (17) (40mg, 8.5%), m.p.159-162 ℃ of .n Max(KBr) 3052,2923,1705,1481,1435,1416,1238,1172,1095,1058,1024cm -1. 1H n.m.r.d 7.65-7.40, m, 18H; 7.30-7.05, m, 22H; 6.58, m, 1H; 6.52, t, J6.6Hz, 1H; 6.39, m, 1H; 6.07, q, J6.6Hz, 1H; 4.73, m, 2H; 3.05, m, 2H. 13C n.m.r.d 159.2 (C), 151.8 (C), 138.3 (CH), 136.5 (C), 134.8 (CH), 133.2 (C), 131.8 (C), 131.5 (C), 131.0 (C), 129.9 (CH), 129.8 (CH), 129.5 (CH), 129.0 (CH), 128.7 (C), 127.8 (CH), 127.5 (CH), 127.2 (CH), 127.0 (CH), 125.7 (CH), 125.0 (CH), 123.2 (C), 123.0 (CH), 121.9 (CH), 121.1 (C), 120.5 (CH), 42.2 (CH 2), 29.7 (CH 2) .Mass spectrum m/z 365 (6) [(M-Pd (PPh 3) 2Br+H) +-]; 277 (26); 272 (32) { [M-C 6H 4OPd (PPh 3) 2Br] +; 262 (100) (Ph 3P +-) .1-phenylpyrrole [2,1-a] isoquinoline 99.9 (18) and 1-[2 '-(2 "-bromophenyl) ethyl also]-4-phenylpyrrole (19)
With dibromide (4) (13mg; 25mmol), trans-two (m-ethanoyl)-two [o-(two-o-tolyl phosphino-) benzyl] two palladiums (II) (Chem., Eur.; J.; 1997,3,1357;) (2.5mg; 2.5mmol) and sodium acetate, anhydrous (6.2mg, 75mmol) the degassing N,N-dimethylacetamide (0.25ml) in solution in nitrogen atmosphere in 140 ℃ the heating 72 hours.Then the refrigerative reaction mixture is diluted the solution of generation salt solution/water (1 of 3 * 5ml: the washing 1v/v mixture) with ether (5ml).With organic phase drying (sal epsom), filter and concentrating under reduced pressure then, provide light yellow oil.Make this material carry out flash chromatography (silica gel, 3: 77: 3 dichloromethane/hexane wash-outs) then, with required fraction (R f0.7,3: 7 dichloromethane/hexane wash-outs) after, the light yellow unsettled oily matter of 1: 3 mixture (4mg, 52% productive rate that merges) of compound (18) and (19) provided.n max(KBr)1705，41.2，1555，1500，1471，1441，1359，1202，1071，1027，751，694，655cm -1. 1H?n.m.r.d[compound(18)]7.60-6.95，complex?m，9H；6.92，t，J2.0Hz，1H，H-2；6.63，t，J1.6Hz，1H，H-5；6.43，broadened?t，J2.3Hz，1H，H-4；4.14，t，J7.7Hz，2H；3.22，t，J7.7Hz，2H；[compound(19)]?7.60-6.95，complex?m，9H；6.73，d，J2.7Hz，1H，H-3；6.23，d，J2.7Hz，1H，H-2；4.08，t，J7.7Hz，2H；3.10，t，J7.7Hz，2H.G.c./m.s.[compound(18)]R f?4.52?min.)245(100)(M +-)，167(21)，149(28)，120(6)；[compound(19)](R f?5.85?min.)327(12)325(12)(M +-)，246(100)[(M-Br -) +].
In whole specification sheets and claims, unless context needs, " comprising " speech and its version are as " comprising ", to be construed as comprising described integral body or step or whole one group, but do not get rid of other integral body then or step or whole one group.
Those skilled in the art should be appreciated that the present invention as herein described is changed easily and improves except the part of special description.Should be appreciated that and the present invention includes these all class changes and improvements.All steps that the present invention is also included within this specification sheets separately or accumulation provides, feature, composition and compound, and two or more said steps or feature and combination arbitrarily.

Claims (32)

1. the method for preparing general formula (II) compound:
Figure A9980786700021
Comprise the intramolecular cyclization step of carrying out formula (I) compound:
Figure A9980786700022
R wherein A1-A4Be selected from hydrogen independently of one another, the alkyl of non-imposed replacement, the thiazolinyl of non-imposed replacement, the alkynyl of non-imposed replacement, the hydroxyl of non-imposed protection, the amino of non-imposed replacement, the alkoxyl group of non-imposed replacement, the alkene oxygen base of non-imposed replacement, the alkynyloxy group of non-imposed replacement, the aryl of non-imposed replacement, the heterocyclic radical of non-imposed replacement, carboxyl, carboxylic ester group, amide group, acyl group, acyloxy, sulfydryl, the alkylthio of non-imposed replacement, halogen, nitro, sulfate radical, phosphate radical and cyano group;
Or R A2And R A3Form a key together non-imposedly, and R A1And R A4As above definition or form the carbocyclic ring or the heterocyclic radical of non-imposed replacement with the carbon atom that it connected; Or
R A2And R A3Form the saturated or unsaturated carbocyclic or the heterocyclic radical of non-imposed replacement with the carbon atom that it connected non-imposedly; Or
R A1R A2C-CR A3R A4Form the aryl or the fragrant heterocyclic radical of non-imposed replacement;
Y is selected from hydrogen, the alkyl of non-imposed replacement, the thiazolinyl of non-imposed replacement, the alkynyl of non-imposed replacement, the hydroxyl of non-imposed protection, the amino of non-imposed replacement, the alkoxyl group of non-imposed replacement, the alkene oxygen base of non-imposed replacement, the alkynyloxy group of non-imposed replacement, the aryl of non-imposed replacement, the heterocyclic radical of non-imposed replacement, carboxyl, the carboxylic ester group, amide group, acyl group, acyloxy, sulfydryl, the alkylthio of non-imposed replacement, halogen, nitro, sulfate radical, phosphate radical and cyano group;
The definition of W and X such as Y perhaps forms saturated or undersaturated nitrogen heterocycle with nitrogen and the carbon atom that it connected, and this heterocyclic radical can be substituted non-imposedly, or non-imposed and saturated or undersaturated carbocylic radical, and aryl or heterocyclic radical condense;
V represents halogen or hydrogen atom;
Z is-(CH 2) n-U-(CH 2) o-wherein U is selected from CH 2, NH or heteroatoms, n and o are independently selected from 0,1, and 2 or 3.
2. according to the method for claim 1, wherein W forms saturated or unsaturated nitrogen heterocycle with X with nitrogen and the carbon atom that they were connected, this heterocyclic radical can be substituted or non-imposed and saturated or unsaturated carbon cyclic group non-imposedly, and aryl or heterocyclic radical condense.
3. according to the method for claim 2, wherein W forms the quinolyl that is selected from non-imposed replacement with X with nitrogen and the carbon atom that they were connected, the isoquinolyl of non-imposed replacement, the dihydroquinoline base of non-imposed replacement, the dihydro-isoquinoline base of non-imposed replacement, the pyridyl of non-imposed replacement or its dihydro or tetrahydrochysene homologue, or the phenanthridines of non-imposed replacement.
4. according to the method for claim 3, the wherein isoquinolyl of W and the X non-imposed replacement that forms formula (i) with nitrogen that they were connected and carbon atom or the dihydro-isoquinoline base of non-imposed replacement: R wherein 1-R 4And R 14As the definition of claim 1 couple Y, and Expression singly-bound or two key.
5. according to the method for claim 4, R wherein 1-R 4Be independently selected from hydrogen; Hydroxyl; The alkyl of non-imposed replacement; The alkoxyl group of non-imposed replacement; Acyloxy; Carboxyl; Carboxyl ester; The amino of non-imposed replacement; Amide group; Or sulfate radical; And R 14Be hydrogen or hydroxyl.
6. the method for preparation formula (IIa) compound:
Figure A9980786700042
Comprise the intramolecular cyclization step of carrying out twice formula (Ia) compound:
Figure A9980786700043
Wherein:
R A1-A4, V, Y, Z such as claim 1 definition;
R B1-B4Be selected from hydrogen independently of one another, the alkyl of non-imposed replacement, the thiazolinyl of non-imposed replacement, the alkynyl of non-imposed replacement, the hydroxyl of non-imposed protection, the amino of non-imposed replacement, the alkoxyl group of non-imposed replacement, the alkene oxygen base of non-imposed replacement, the alkynyloxy group of non-imposed replacement, the aryl of non-imposed replacement, the heterocyclic radical of non-imposed replacement, carboxyl, carboxyl ester, amide group, acyl group, acyloxy, sulfydryl, the alkylthio of non-imposed replacement, halogen, nitro, sulfate radical, phosphate radical and cyano group; Or
R B2And R B3Form a key together non-imposedly, and R A1And R A4As above definition or form the carbocyclic ring or the heterocyclic radical of non-imposed replacement with the carbon atom that it connected; Or
R B2And R B3Form the saturated or unsaturated carbocyclic or the heterocyclic radical of non-imposed replacement with the carbon atom that it connected; Or
R B1R B2C-CR B3R B4Form the aryl or the fragrant heterocyclic radical of non-imposed replacement; And
M is selected from 1,2, and 3 or 4.
7. according to the method for claim 6, wherein m is 1 or 2, preferred 2.
8. according to the method for claim 1 or claim 6, R wherein A1R A2C-CR A3R A4Form aryl or fragrant heterocyclic radical, said group is selected from: the benzene of non-imposed replacement or naphthalene nucleus, or the pyridine of non-imposed replacement, the furans of non-imposed replacement, the pyrroles of non-imposed replacement or the thiophene of non-imposed replacement and its benzene-condensed analogue.
9. method according to Claim 8, wherein R A1R A2C-CR A3R A4Form the phenyl of non-imposed replacement.
10. according to the method for claim 9, wherein substituting group is selected from: hydrogen; Hydroxyl; The alkyl of non-imposed replacement; The alkoxyl group of non-imposed replacement; Acyloxy; Carboxyl; Carboxyl ester; The amino of non-imposed replacement; Amide group; Or sulfate radical.
11. according to the method for claim 1 or 6, wherein Y is the phenyl of formula non-imposed replacement (ii):
R wherein 9-R 13As in the claim 4 to R 1-R 4Definition.
12. according to the method for claim 11, wherein R 9-R 13Be independently selected from hydrogen; Hydroxyl; The alkyl of non-imposed replacement; The alkoxyl group of non-imposed replacement; Acyloxy; Carboxyl; Carboxyl ester; The amino of non-imposed replacement; Amide group; Or sulfate radical.
13. according to the method for claim 10, wherein R 9-R 13Be independently selected from hydrogen, hydroxyl, methoxyl group, oxyethyl group, isopropoxy, methyl, ethyl, n-propyl, sec.-propyl, acetoxyl group or sulfate radical.
14. thick many rings of preparation formula (IIb) contain the method for azole compounds: Comprise that formula (Ib) compound carries out the step of twice intramolecular cyclization:
Figure A9980786700062
Wherein V is halogen or hydrogen, and R 1-14Be independently selected from hydrogen, the alkyl of non-imposed replacement, the thiazolinyl of non-imposed replacement, the alkynyl of non-imposed replacement, the hydroxyl of non-imposed protection, the amino of non-imposed replacement, the alkoxyl group of non-imposed replacement, the alkene oxygen base of non-imposed replacement, the alkynyloxy group of non-imposed replacement, the aryl of non-imposed replacement, the heterocyclic radical of non-imposed replacement, carboxyl, carboxyl ester, amide group, acyl group, acyloxy, sulfydryl, the alkylthio of non-imposed replacement, halogen, nitro, sulfate radical, phosphate radical and cyano group; With
Make the cyclisation product dehydrogenation non-imposedly, form wherein dispensable pair key
Figure A9980786700071
Formula (Ib) compound that exists.
15. according to the method for claim 14, wherein R 1-14Be independently selected from: hydrogen; Hydroxyl; The alkyl of non-imposed replacement; The alkoxyl group of non-imposed replacement; Acyloxy; Carboxyl; Carboxyl ester; The amino of non-imposed replacement; Amide group; Or sulfate radical, preferably, R 1-13Be selected from hydrogen; Hydroxyl; The alkyl of non-imposed replacement, as methyl, ethyl or propyl group; The alkoxyl group of non-imposed replacement such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy; Acyloxy such as acetoxyl group; Or sulfate radical, and R 14Preferably hydrogen or hydroxyl, V is a bromine, iodine or hydrogen.
16. according to the method for claim 1 or 6, wherein U is selected from CH as defining in Z 2, NH or oxygen, preferred oxygen, and n+o=0,1,2,3 or 4, preferred 0.
17. according to the method for claim 1 or 6 or 14, wherein each V is hydrogen independently, bromine or iodine.
18. according to the process of claim 1 wherein that V is a hydrogen, and cyclisation is carried out under oxidizing condition.
19. according to the process of claim 1 wherein that V is a halogen atom, preferred bromine or iodine, and cyclisation is carried out through the generation of formula (I) group.
20. according to the process of claim 1 wherein that V is a halogen atom, preferred bromine or iodine, and cyclisation is through Pd[O]-catalytic method and carrying out.
21. according to the method for claim 6 or 14, wherein two V are halogens, preferred bromine or iodine, and twice cyclisation carried out in one pot.
22. according to the method for claim 21, wherein one pot of dicycloization is Pd[O]-catalytic.
23. the compound of formula (I):
Figure A9980786700081
Wherein:
R A1-A4Be selected from hydrogen independently of one another, the alkyl of non-imposed replacement, the thiazolinyl of non-imposed replacement, the alkynyl of non-imposed replacement, the hydroxyl of non-imposed protection, the amino of non-imposed replacement, the alkoxyl group of non-imposed replacement, the alkene oxygen base of non-imposed replacement, the alkynyloxy group of non-imposed replacement, the aryl of non-imposed replacement, the heterocyclic radical of non-imposed replacement, carboxyl, carboxyl ester, amide group, acyl group, acyloxy, sulfydryl, the alkylthio of non-imposed replacement, halogen, nitro, sulfate radical, phosphate radical and cyano group; Or
R A2And R A3Form a key together non-imposedly, and R A1And R A4As above definition or form the carbocyclic ring or the heterocyclic radical of non-imposed replacement with the carbon atom that it connected; Or
R A2And R A3Form the saturated or unsaturated carbocyclic or the heterocyclic radical of non-imposed replacement with the carbon atom that it connected non-imposedly; Or
R A1R A2C-CR A3R A4Form the aryl or the fragrant heterocyclic radical of non-imposed replacement;
Y is selected from hydrogen, the alkyl of non-imposed replacement, the thiazolinyl of non-imposed replacement, the alkynyl of non-imposed replacement, the hydroxyl of non-imposed protection, the amino of non-imposed replacement, the alkoxyl group of non-imposed replacement, the alkene oxygen base of non-imposed replacement, the alkynyloxy group of non-imposed replacement, the aryl of non-imposed replacement, the heterocyclic radical of non-imposed replacement, carboxyl, carboxyl ester, amide group, acyl group, acyloxy, sulfydryl, the alkylthio of non-imposed replacement, halogen, nitro, sulfate radical, phosphate radical and cyano group;
The definition of W and X such as Y perhaps forms saturated or undersaturated nitrogen heterocycle with nitrogen and the carbon atom that it connected, and this heterocyclic radical can be substituted non-imposedly, or non-imposed and saturated or undersaturated carbocylic radical, and aryl or heterocyclic radical condense;
V represents halogen or hydrogen atom;
Z is-(CH 2) n-U-(CH 2) o-wherein U is selected from CH 2, NH or heteroatoms, n and o are independently selected from 0,1, and 2 or 3.
24. according to the compound of claim 23, wherein definition in any of W and X such as the claim 2 to 5.
25. formula (Ia) compound:
Figure A9980786700091
Wherein:
R A1-A4, R B1-B4, V, Y, definition in Z and m such as the claim 6.
26. according to the compound of claim 23 or 25, wherein R A1R A2C-CR A3R A4Form the phenyl of non-imposed replacement.
27. formula (Ib) compound:
R wherein 1-14Be independently selected from hydrogen, the alkyl of non-imposed replacement, the thiazolinyl of non-imposed replacement, the alkynyl of non-imposed replacement, the hydroxyl of non-imposed protection, the amino of non-imposed replacement, the alkoxyl group of non-imposed replacement, the alkene oxygen base of non-imposed replacement, the alkynyloxy group of non-imposed replacement, the aryl of non-imposed replacement, the heterocyclic radical of non-imposed replacement, carboxyl, carboxyl ester, amide group, acyl group, acyloxy, sulfydryl, the alkylthio of non-imposed replacement, halogen, nitro, sulfate radical, phosphate radical and cyano group; With
V is halogen or hydrogen.
28. according to the compound of claim 27, wherein R 1-14Be independently selected from: hydrogen; Hydroxyl; The alkyl of non-imposed replacement; The alkoxyl group of non-imposed replacement; Acyloxy; Carboxyl; Carboxyl ester; The amino of non-imposed replacement; Amide group; Or sulfate radical, preferably R 1-13Be independently selected from hydrogen; Hydroxyl; The alkyl of non-imposed replacement, as methyl, ethyl or propyl group; The alkoxyl group of non-imposed replacement such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy; Acyloxy such as acetoxyl group; Or sulfate radical, and R 14Preferably hydrogen or hydroxyl; V is a bromine, iodine or hydrogen.
29. the method for the tumour of treatment multiple medicines thing tolerance comprises the animal to needs, comprises the method preparation as described herein of people's administering therapeutic significant quantity, the formula any according to claim 1,6 or 14 (II), (IIa) or (IIb) compound.
30. method as described herein preparation, the formula any (II) according to claim 1,6 or 14, (IIa) or (IIb) compound is used for the treatment of purposes in the medicine of tumour of multiple medicines thing tolerance in production.
31. a medicament for the treatment of multiple medicines thing tolerance tumour comprises method preparation as described herein, the formula any according to claim 1,6 or 14 (II), (IIa) or (IIb) compound.
32. the composition of treatment multiple medicines thing tolerance tumour comprises method preparation as described herein, the formula any according to claim 1,6 or 14 (II), (IIa) or (IIb) compound, and pharmaceutical carrier, thinner or vehicle.
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